Are You Confident of the Diagnosis?

What you should be alert for in the history

Acanthosis nigricans (AN) is a skin disease characterized by symmetric, velvety, hyperpigmented plaques that may occur in any location of the body. Given the association between AN and various systemic abnormalities, (including insulin resistance, obesity, hyperandrogenism, malignancy, and various syndromes) clinicians should be alert for several findings in the history of patients with this skin disease.

Insulin resistance is usually asymptomatic; however, studies have shown a weak association with depressive symptoms. Symptoms of cutaneous virilism due to hyperandrogenism include hirsutism, acne vulgaris, hidradenitis suppurativa and androgenic alopecia. A medication history is important, as several drugs have been associated with AN. Nicotinic acid is the medication most commonly associated with AN; however. oral contraceptives, heroin, corticosteroids, diethylstilbestrol, methyltestosterone and fusidic acid have also been reported culprits causing AN. Unintentional weight loss, fevers, night sweats, or a constellation of other nonspecific symptoms should alert a malignancy work-up.

Characteristic findings on physical examination

Acanthosis nigricans (AN) is a skin disease characterized by symmetric, velvety, hyperpigmented plaques that may occur in any location of the body. Lesions are most commonly found on the lateral and posterior neck, axilla, and groin, although other locations may include: elbows, knuckles, and face, particularly in patients with darkly pigmented skin. Acanthosis nigricans may be benign or malignant (ie, cancer-related). The nonmalignant types of AN include: idiopathic or benign, obesity-related, syndromic, unilateral/nevoid, acral AN, drug-induced, and mixed (Figure 1,Figure 2, Figure 3, Figure 4, Figure 5, Figure 6, Figure 7, Figure 8).

Figure 1.

AN of neck.

Figure 2.

Inflamed AN of neck.

Figure 3.

AN with acrochordons in the axilla.

Figure 4.

Elbow AN.

Figure 5.

Acral AN.

Figure 6.

AN on zygomatic arch.

Figure 7.

Periorbital AN.

Figure 8.

Intertriginous AN.

Obese individuals may have maxillary or periorbital involvement; however, these locations are more common in patients with generalized or malignancy-associated AN. Acrochordons frequently occur concomitantly with AN. Malignancy-associated AN involves the mucosa and often presents with systemic signs of malignancy such as progressive unintentional weight loss. Tripe palms (accentuation of the palmar ridges, in addition to AN involving the eyelids, lips and genitals, are also characteristic findings of malignant AN. (Figure 9)

Figure 9.

Tripe palm.

Expected results of diagnostic studies

Skin biopsy may be performed to help solidify a diagnosis. Histopathologically, all forms of AN demonstrate epidermal hyperkeratosis, papillomatosis and minimal to mild acanthosis. Rather than pigment-producing cells, epidermal papillomatosis and acanthosis are responsible for the hyperpigmentation observed in AN (Figure 10A and Figure 10B). Serologic examination is performed after the AN type is established. Serum examination detecting insulin receptor serum autoantibodies, rheumatological antibodies such as ANA, and serum androgens such as DHEA-S, 17-hydroxyprogesterone, total testosterone, prolactin, FSH, and LH may be obtained in patients with syndromic AN. Fasting serum insulin and glucose levels, HbA1C, a fasting lipid profile, and blood pressure should be checked in patients with syndromic, obesity-associated and benign AN. Age and gender-appropriate malignancy screening should be performed in patients with suspected malignant AN which may include: CT scans of the chest, abdomen and pelvis, endoscopy, colonoscopy, mammogram, and pelvic exam. The most commonly associated malignancies will be discussed below.

Although potentially clinically similar in presentation, histologically, psoriasis and AN are easily distinguishable. CARP papules may form confluent plaques centrally however. unlike AN, papules reticulate at the periphery. Like AN, CARP lesions may also form on the neck; however, lesions may also appear in the interscapular area, abdomen, and inframammary region, which is not characteristic of AN.

Unlike the velvety plaques seen in AN, Dowling-Degos or reticulate pigmented anomaly presents as papules or macules. Additionally, lesions may be pruritic, which is not typical of AN. Although PV may also occur in flexural areas, unlike AN, PV lesions often present as bullae or pustules. RH may also present in similar locations although, unlike AN, RH is easily treated with keratolytics.

Who is at Risk for Developing this Disease?

Obese patients with associated insulin resistance are the most likely population to develop AN. Additionally, AN may be a sign of developing metabolic syndrome or concomitant existence of diabetes, hypertension and central obesity. Independent of body mass index (BMI), AN indicates insulin sensitivity in the affected individual.

The prevalance of AN is reported as high as 18.6% in the child and adolescent population. In the pediatric population, the incidence of AN has paralleled the increase in childhood obesity and associated insulin resistance. In fact, AN was established as a criterion for identifying children at risk for developing diabetes mellitus in 2000 by the American Diabetes Association. Given the high prevalance of obesity, malignancy-associated AN is less common, however, it represents an important paraneoplastic syndrome.

What is the Cause of the Disease?

Etiology

Pathophysiology

Several mechanisms to explain the pathogenesis of AN have been proposed, all of which consider enhanced cellular proliferation. Hyperinsulinemia present in benign AN results in a decreased number of functional insulin receptors which, via tyrosine kinase activity, regulate glucose uptake, cell growth, DNA synthesis, and protein/fat metabolism. Insulin may also bind to insulin-like growth factor (IGF) receptors resulting in enhanced cellular growth. These receptors are expressed by both keratinocytes and fibroblasts. The decreased number of functional insulin receptors results in increased binding to IGF receptors thus contributing toward the cutaneous lesions of AN.

Malignant AN may result from direct expression of cellular proliferation-enhancing peptides by tumor cells, which include: transforming growth factor-alpha and epidermal growth factor. Fibroblast growth factor receptor 3 (FGFR3) has also been associated with formation of AN, including malignant AN. Acanthosis nigricans associated with hereditary diseases and FGFR3 germline mutations may be due to the resultant proliferative effect on keratinocytes. Tumor growth factor-alpha, ERK (a mitogen-activated protein kinase) and activation of insulin-like growth factor receptor have been suggested as contributing factors toward AN development.

Systemic Implications and Complications

As previously mentioned, there are several systemic disorders associated with AN. Obesity, hyperinsulinemia, and the metabolic syndrome are the most commonly associated disorders. Fasting serum insulin and glucose levels, and a fasting lipid profile should be checked in patients with syndromic, obesity-associated and benign AN. Treatment targeting toward improving the insulin resistance state, such as a low calorie diet and weight reduction, may decrease the severity of skin disease.

Numerous rare syndromes are associated with AN (for a complete listing of all related syndromes, refer to Table II in reference 2). Type A and B insulin resistance syndromes are the most commonly associated syndromes, both of which are associated with hyperinsulinemia. The Type A insulin resistance syndrome, otherwise known as HAIR-AN, includes concomitant existence of hyperandrogenism, insulin resistance, and AN. It is caused by genetic defects resulting in mutations in the insulin-signaling system and most commonly affects women, especially young African Americans.

Generalized lipodystrophy syndromes, including the congenital Berardinelli-Seip and acquired Lawrence syndromes have also been associated with AN. Both syndromes involve the complete absence of subcutaneous fat causing extreme insulin resistance and hyperandrogenism. Acanthosis nigricans may also occur with polycystic ovary syndrome or in a triad with polycystic ovaries and hirsutism. In the latter clinical triad, the vulva is the most commonly affected area of the body.

Age-appropriate malignancy screening should be performed in patients with suspected malignant AN. Rapid onset of skin lesions in patients over the age of 40 should alert clinicians that malignancy may be the cause of AN. The most commonly associated malignancy is gastric adenocarcinoma and the majority (60%) of patients present with concomitant skin lesions and malignancy. Malignant AN has also been reported with endometrial carcinoma, lung cancer, hepatocellular carcinoma, pancreatic adenocarcinoma, ovarian carcinoma and squamous cell carcinoma of the cervix. The course of AN correlates directly with the associated malignancy; therefore, skin lesions should resolve with its eradication.

Treatment Options

As described under the optimal therapeutic approach section, treatment of AN varies depending upon the type. AN, especially malignancy-associated, is often difficult to treat and no gold standard therapy exists. Topical therapies commonly cause skin irritation without clinical benefit.

Rituximab 750mg/meter IV body surface area in 2 consecutive doses 2 weeks apart (once cyle) and then every 3-4 months if active disease + Oral Cyclophosphamide 100mg daily until remission + Oral dexamethasone 40mg daily for 4 days or Methylprednisone 1gm IV for 2 days given with each rituximab dose and then every 4-6 weeks if active disease remained

Malignant

Systemic therapy

Treat underlying malignancy

Isotretinoin 10mg daily (case report), palliative

Patient Management

Although well established for diabetes mellitus, Hemoglobin A1C has not been studied to monitor response to glucose-improving therapies for AN. No gold standard treatment for AN exists; however, the literature supports metformin for the treatment of obesity-associated AN. Additionally, although not well studied, topical therapies may also be used in addition to systemic therapy. The importance of diet and exercise in combination with the above therapy should also be stressed to patients.

Unusual Clinical Scenarios to Consider in Patient Management

Acanthosis nigricans may present in atypical locations such as the face, the extensor surfaces of the elbows and knees, and dorsum of the feet. The metabolic hormone leptin may contribute toward cell proliferation, growth and apoptosis of epithelial cells. However, its role in AN remains unclear. Additionally, it is unknown if AN present in the above atypical areas responds differently to therapy.

What is the Evidence?

(Dr. Gil Yosipovitch, a faculty member at Wake Forest Univeristy Department of Dermatology, discusses the importance of acanthosis nigricans as a cutaneous manifestation of obesity in this CME article for JAAD. This article points out several key clinical associations between AN and other cutaneous/endocrinologic diagnoses, specifically: the clinical triad of polycystic ovaries, hirsutism, and AN and also cutaneous virilism, AN, keratosis pilaris and insulin resistance. Additionally, a pathophysiologic mechanism of how hyperinsulineamia causes AN is explained. IGF receptors are present on both keratinocytes and fibroblasts and may bind insulin and have growth-promoting effects. Hyperinsulinemia causes a decreased number of functional insulin receptors which results in increased binding to IGF and thus contributing toward the development of AN.)

(Dr. Schwartz, the director of dermatology at New Jersey Medical School, has several publications on AN. In their article on juvenile AN he and Dr. Sinha have nicely outlined the epidemiology, pathogenesis, clinical manifestations and treatments for AN. Table II is an excellent list of syndromes associated with AN and is referenced in the "systemic implications and complications" section of the above chapter. In addition to the pathogenic mechanism outlined in Dr. Yosipovitch's paper, this manuscript also explains that insulin receptor mutations and lamin A/C gene mutations are the cause of a decreased number of functional insulin receptors.)

(Dr. Benavides is an assistant professor of pharmacy in Florida. She and Dr. Romo have published a comprehensive review that outlines the clinical evidence of various systemic and topical therapies in the treatment of insulin resistance obesity-related AN (IRORAN). Treatment should target the underlying hyperinsulinemia. Metformin demonstrates the most evidence for the efficacy in AN therapy.)

(A total of 287 subjects (236 with AN and 51 without AN) between the ages of 8 and 14 underwent a questionnaire, a targeted physical exam, and an oral glucose tolerance test. The study results demonstrate that youth, in the age group above, with AN have significant insulin resistance and more than 25% will already have evidence of abnormal glucose homeostasis. The three independent risk factors for having impaired glucose tolerance in their subjects with AN are: severe insulin resistance, female sex, and GAD (glutamic acid decarboxylase) autoimmunity and coincide with previously established risk factors for the development of diabetes.)

(Although most commonly associated with gastric adenocarcinoma, AN is among the nine most common paraneoplastic and metastatic cutaneous manifestations of malignancies found in women with gynecologic or breast disease. Important to recognize early, malignant AN often manifests at the same time as the associated malignancy. The course of malignant AN correlates closely with the course of the underlying malignancy.)

(Dr. Balasubramanyam is a professor of medicine in the Division of Diabetes, Endocrinology and Metabolism at Baylor College of Medicine and has a research interest in syndromes of ketosis-prone diabetes. Although rare, Type B insulin resistance is a syndrome commonly associated with AN. After failed therapy with increasing doses of metformin, and then combination therapy with rosiglitazone and later isophane insulin suspension, the patient was able to achieve clinical remission after a 10-day course of oral cyclophosphamide 150 mg daily. Serologic testing also revealed the temporal association between the resolution of AN lesions and the disappearance of anti-insulin receptor antibodies during her course of cyclophosphomide therapy.)

(This article reviews the common clinical features, pathophysiology, laboratory findings and treatment options for AN. In addition to discussing the role of the IGF receptor in the formation of AN this article also mentions defects in fibroblast growth factor receptor type 3 in several syndromes associated with AN which is the focus of the study by Hida et al referenced below. Dietary control and physical exercise are also stressed as important contributions toward the improvement of insulin sensitivity and the prevention of type 2 DM.)

(Cross-sectional data was collected from a population-based cohort study in Hoorn, a town in the Netherlands, in order to determine the strength of association between depressive symptoms and insulin resistance. The homeostasis model assessment for insulin resistance (HOMA-IR) and Centre for Epidemiologic Studies Depression Scale (CES-D) were utilized to determine insulin resistance and symptoms of depression respectively. A total of 541 men and women, of whom 164 had impaired glucose tolerance, were included in the study sample size. Although weak, an association between depressive symptoms and insulin resistance was found.)

(Acanthosis nigricans is difficult to treat and no gold standard topical therapy exists. In this case report, an 85-95% improvement in AN lesions (decrease in hyperkeratosis and hyperpigmentation) was found after a 4-month course of 12% ammonium lactate cream or lotion twice daily in combination with tretinoin 0.05% cream at bedtime. Interestingly, neither of the above topical therapies were beneficial alone.)

(Researchers from the Department of Dermatology at the Univerisity of Tokushima Graduate School and Ehime University School of Medicine in Japan compared the expression of fibroblast growth factor receptor 3 (FGFR3) in two cases of malignant AN to that in 20 samples of normal skin using immunohistochemical analysis. The epidermis demonstrated a strong expression of FGFR3 in both cases of malignant AN while FGFR3 immunoreactivity was negative to moderately positive in normal epidermis.)